RGD Reference Report - Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage. - Rat Genome Database

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Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage.

Authors: Schulz, Angela  Müller, Nicola Victoria  van de Lest, Nina Anne  Eisenreich, Andreas  Schmidbauer, Martina  Barysenka, Andrei  Purfürst, Bettina  Sporbert, Anje  Lorenzen, Theodor  Meyer, Alexander M  Herlan, Laura  Witten, Anika  Rühle, Frank  Zhou, Weibin  de Heer, Emile  Scharpfenecker, Marion  Panáková, Daniela  Stoll, Monika  Kreutz, Reinhold 
Citation: Schulz A, etal., Elife. 2019 Mar 22;8. pii: 42068. doi: 10.7554/eLife.42068.
RGD ID: 15023481
Pubmed: PMID:30900988   (View Abstract at PubMed)
PMCID: PMC6478434   (View Article at PubMed Central)
DOI: DOI:10.7554/eLife.42068   (Journal Full-text)

Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein Tmem63c as a novel potential target. Tmem63c is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for tmem63c in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as Tmem63c for further translational investigation.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MWF.SHR-(D6Rat1-D6Rat81)/RkbRatAlbuminuria  IAGP compared to MWF.SHR-(D6Rat1-D6Mgh4)RGD 
MWF/FubRkbRatAlbuminuria  IAGP compared to SHR more ...RGD 
TMEM63CHumanAlbuminuria  ISOTmem63c (Rattus norvegicus)mRNA:increased expression:kidney and renal glomerulus (rat)RGD 
Tmem63cRatAlbuminuria  IEP mRNA:increased expression:kidney and renal glomerulus (rat)RGD 
Tmem63cMouseAlbuminuria  ISOTmem63c (Rattus norvegicus)mRNA:increased expression:kidney and renal glomerulus (rat)RGD 
NPHS1Humanfocal segmental glomerulosclerosis  IEP protein:decreased expression:kidney and renal glomerulus (human)RGD 
Nphs1Ratfocal segmental glomerulosclerosis  ISONPHS1 (Homo sapiens)protein:decreased expression:kidney and renal glomerulus (human)RGD 
Nphs1Mousefocal segmental glomerulosclerosis  ISONPHS1 (Homo sapiens)protein:decreased expression:kidney and renal glomerulus (human)RGD 
TMEM63CHumanfocal segmental glomerulosclerosis  IEP protein:decreased expression:kidney and renal glomerulus (human)RGD 
Tmem63cRatfocal segmental glomerulosclerosis  ISOTMEM63C (Homo sapiens)protein:decreased expression:kidney and renal glomerulus (human)RGD 
Tmem63cMousefocal segmental glomerulosclerosis  ISOTMEM63C (Homo sapiens)protein:decreased expression:kidney and renal glomerulus (human)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Tmem63cRatglomerular filtration involved_inIMP PMID:30900988UniProt 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MWF.SHR-(D6Rat1-D6Rat81)/RkbRatdecreased renal glomerulus number  IAGP compared to MWF.SHR-D6Rat1-D6Mgh4RGD 
MWF/FubRkbRatdecreased renal glomerulus number  IAGP compared to SHR more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Nphs1  (NPHS1 adhesion molecule, nephrin)
Tmem63c  (transmembrane protein 63c)

Genes (Mus musculus)
Nphs1  (nephrosis 1, nephrin)
Tmem63c  (transmembrane protein 63c)

Genes (Homo sapiens)
NPHS1  (NPHS1 adhesion molecule, nephrin)
TMEM63C  (transmembrane protein 63C)

Strains
MWF.SHR-(D6Rat1-D6Rat81)/Rkb  (NA)
MWF/FubRkb  (Munich Wistar Fromter)

Objects referenced in this article
Strain MWF.SHR-(D6Rat1-D6Mgh4)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Mit8)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat106)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat115)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat121)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat184)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat30)/Rkb null Rattus norvegicus

Additional Information